The background of the invention relates to diseases that are caused by the human papillomavirus (HPV), in particular cervical cancer and its precursors.
In Germany alone each year about 1 million pathological findings are recorded in women with respect to HPV-induced neoplastic changes in the cervix (cervix uteri). Among a large portion of the women affected, the lesion heals without further measures within the course of a few weeks to months. However, if spontaneous healing does not occur and the development of severe dysplastic epithelial changes takes place, due to the increased risk of a progression to cervical carcinoma the surgical removal of the affected area (conisation) is recommended on the part of the physician. Currently for women with higher grade cervical intraepithelial neoplasia (CIN) there is no therapeutic alternative to the surgical removal of the dysplastic epithelium (conisation). Every year about 150,000 women in Germany have to undergo a conisation. For the women affected, these procedures are not only stressful, but in the case of later pregnancies they also increase the risk of premature birth. The prophylactic inoculation with the newly developed vaccines Gardasil® (Merck) and Cervarix® (GlaxcoSmithKline), also recently introduced in Germany, among young people who have not yet had sexual intercourse reliably prevents a first infection with HPV 6, 11, 16 and 18 (with Gardasil®). However, if a person is already infected with HPV viruses, the vaccine no longer has any affect. Accordingly, its prophylactic effectiveness for preventing cervical intraepithelial neoplasia (CIN lesions) among 25-year old women regardless of the causative HPV serotype is only 17%. Since the first disease peak in the case of cervical carcinoma is between the ages of 35 and 40, even with a broad application of a prophylactic inoculation it will still take about 20 years until the effect of the inoculation has a noticeable influence on the incidence of cervical carcinoma. The necessity of regular screening checkups and the desire for effective, gentler therapeutic measures will continue despite the introduction of the prophylactic inoculation.
The cause of the development of cervical dysplasia is persistent infection are high-risk papillomavirus. Among young women in the age group between 20 and 30 the incidence of high-risk HPV infections is almost 50% (for instance in Denmark). Subsequently, infected women regularly develop cytological symptoms with the so-called cervical smear (pap smear) or dysplastic changes in the sense of a cervical intraepithelial neoplasia (CIN) up to cervical carcinoma. Although the cause of the dysplastic changes is a virus infection, the immunological defensive reaction is often delayed or is inadequate in its effect, so that protracted infections occur that can extend over periods of months to several years. The reason for the inadequate immunological defensive reaction is low replication rates and consequently only low quantities of viral antigens, which reach the target organism and additionally effective HPV mechanisms for suppressing immunological defensive reactions. Since papillomaviruses in particular infect cells of the so-called transformation zone in the region of the cervix uteri, the induced tissue changes are usually limited to the region of the distal channel of the cervix and central portions of the portio uteri.
In the prior art, furthermore, methods can be found for the destruction of HPV oncoprotein expressing cells, which are suitable for the prophylaxis and/or treatment of HPV-induced diseases, such as for instance cervical cancer and its precursors.
Thus WO 2009/106362 A1 describes a selection method for nucleic acids that code for one or more human papillomavirus (HPV) oncoproteins and/or fragments thereof. The object of WO 2009/106362 A1 is to create an allegedly safe vaccine in that it has only antigen sequence motifs, that is, all the other sequence motifs like those with transformation-associated peptide motifs from the DNA of the vaccine were previously removed by cloning measures. A nucleic acid of this type after expression is to be able to induce an immune response in a mammalian organism that leads to the destruction of HPV oncoprotein expressing cells and thus is suitable for the prophylaxis and/or treatment of HPV-induced diseases, such as cervical cancer and its precursors.
Hoffmann et al. (J. Immunother 2010; 33; 136-145) describe a similar approach to the treatment of HPV-induced diseases with a recombinant DNA vaccine, namely an adenovirus based T-cell vaccine in which the problematic sequence motifs were detected, which are to cause a specific T cell response in vivo.
These methods have in common that they relate to vaccination agents, that is, vaccines that directly reach the bloodstream.